title: A Genome-Wide Association Study Suggests Novel Loci Associated with a Schizophrenia-Related Brain-Based Phenotype.
abstract: Patients with schizophrenia and their siblings typically show subtle changes of brain structures, such as a reduction of hippocampal volume. Hippocampal volume is heritable, may explain a variety of cognitive symptoms of schizophrenia and is thus considered an intermediate phenotype for this mental illness. The aim of our analyses was to identify single-nucleotide polymorphisms (SNP) related to hippocampal volume without making prior assumptions about possible candidate genes. In this study, we combined genetics, imaging and neuropsychological data obtained from the Mind Clinical Imaging Consortium study of schizophrenia (n = 328). A total of 743,591 SNPs were tested for association with hippocampal volume in a genome-wide association study. Gene expression profiles of human hippocampal tissue were investigated for gene regions of significantly associated SNPs. None of the genetic markers reached genome-wide significance. However, six highly correlated SNPs (rs4808611, rs35686037, rs12982178, rs1042178, rs10406920, rs8170) on chromosome 19p13.11, located within or in close proximity to the genes NR2F6, USHBP1, and BABAM1, as well as four SNPs in three other genomic regions (chromosome 1, 2 and 10) had p-values between 6.75×10(-6) and 8.3×10(-7). Using existing data of a very recently published GWAS of hippocampal volume and additional data of a multicentre study in a large cohort of adolescents of European ancestry, we found supporting evidence for our results. Furthermore, allelic differences in rs4808611 and rs8170 were highly associated with differential mRNA expression in the cis-acting region. Associations with memory functioning indicate a possible functional importance of the identified risk variants. Our findings provide new insights into the genetic architecture of a brain structure closely linked to schizophrenia. In silico replication, mRNA expression and cognitive data provide additional support for the relevance of our findings. Identification of causal variants and their functional effects may unveil yet unknown players in the neurodevelopment and the pathogenesis of neuropsychiatric disorders.
authors.affiliation: Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden University of Technology, Dresden, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Hass
authors.forename: Esther
authors.initials: E
authors.lastname: Walton
authors.forename: Holger
authors.initials: H
authors.lastname: Kirsten
authors.forename: Jingyu
authors.initials: J
authors.lastname: Liu
authors.forename: Lutz
authors.initials: L
authors.lastname: Priebe
authors.forename: Christiane
authors.initials: C
authors.lastname: Wolf
authors.forename: Nazanin
authors.initials: N
authors.lastname: Karbalai
authors.forename: Randy
authors.initials: R
authors.lastname: Gollub
authors.forename: Tonya
authors.initials: T
authors.lastname: White
authors.forename: Veit
authors.initials: V
authors.lastname: Roessner
authors.forename: Kathrin U
authors.initials: KU
authors.lastname: Müller
authors.forename: Tomas
authors.initials: T
authors.lastname: Paus
authors.forename: Michael N
authors.initials: MN
authors.lastname: Smolka
authors.forename: Gunter
authors.initials: G
authors.lastname: Schumann
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Vince
authors.initials: V
authors.lastname: Calhoun
authors.forename: Stefan
authors.initials: S
authors.lastname: Ehrlich
mesh_terms: D000293:Adolescent; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000378:metabolism; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism